1. Field of the Invention
The present invention relates to the compositions for treating asthma, allergy and inflammation, and particularly to a pair of enhydrazone esters that may be used effectively in the treatment of asthma, allergy and inflammation.
2. Description of the Related Art
Drugs having anti-asthma and anti-allergic effects are well known, but such drugs are typically either bronchodilators or inhibitors, or work through the inhibition of the release of allergic mediators or inflammatory mediators. Due to the important role that eosinophils play in allergies, allergy-related diseases and asthma, drugs that have direct inhibitory effect on these cells are widely believed to hold a high potential for the effective treatment of these diseases. Previous studies, however, have shown that no existing clinically used anti-allergy or anti-asthmatic drugs, at clinically relevant concentrations, have any significant direct inhibitory effect on eosinophil degranulation.
Allergic diseases (e.g., asthma, allergic rhinitis, urticaria, atopic eczema and dermatitis) are experienced by up to 25% of the population, and the prevalence of these conditions appears to be increasing worldwide. Eosinophils and mast cells are the two most important pro-inflammatory cells involved in the pathophysiology of asthma and other allergic diseases. The degranulation of these cells and the release of many mediators, including tissue-damaging proteins, by eosinophils orchestrate the inflammation that underlies these diseases.
The primary trigger of allergic diseases is the interaction between an allergen and the specific immunoglobulin E (IgE) molecules bound to the high affinity IgE receptor (FcεRI) on the surface of mast cells of sensitized patients. This results in the degranulation of these cells and the consequent release of pre-formed allergic and inflammatory mediators, such as histamine, tryptase and various enzymes. In addition, other mediators, such as eicosanoids (e.g., leukotrienes) and cytokines (especially TNF-α, IL-4, IL-13 and GM-CSF), are synthesized and released on activation. All of these mediators participate in the pathophysiology of the diseases.
Like the mast cells, eosinophils are also intimately involved in the pathophysiology of asthma. Histologically, the asthmatic lung is heavily infiltrated by eosinophils, which are believed to degranulate at the site to release mediators that contribute to bronchial inflammation, airway hyperresponsiveness, and airway tissue remodeling. Eosinophil granules contain several cationic proteins, such as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase (EPO), which are directly toxic to many tissues. The released cationic proteins are believed to damage, in particular, the epithelium leading to bronchial hyperresponsiveness that is so characteristic of asthma. In fact, sputum eosinophil count, as well as the level of eosinophil cationic protein, has been shown to be a reliable indicator of disease severity or exacerbation. Furthermore, results from studies employing eosinophil-deficient mice strongly support an important role for eosinophils in asthma.
Drugs used as inhibitors of mast cell degranulation, such as cromolyn sodium and nedocromil sodium, are used in the treatment of asthma and other allergic diseases. Drugs that may inhibit eosinophil accumulation or inhibit cytokine generation, such as steroids, are also used as anti-asthma and anti-allergic drugs. However, no currently available drug has the ability to directly inhibit the degranulation of both mast cells and eosinophils.
Even steroids, which are the current mainstay of antiinflammatory therapy, lack an acute and direct effect on degranulation of these cells. Steroids also have many side effects.
Drugs that combine the ability to directly inhibit the degranulation of both mast cells and eosinophils at clinically relevant concentrations would be highly desirable for the treatment of asthma and other allergy-related diseases and conditions.
Thus, enhydrazone esters for treating asthma, allergy, and inflammation solving the aforementioned problems are desired.